Download Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia

Review Article
Oncol Res Treat 2015;38:596–603
DOI: 10.1159/000441310
Received: August 18, 2015
Accepted: September 28, 2015
Published online: October 20, 2015
Patients with Advanced Pancreatic Cancer and
Hyperbilirubinaemia: Review and German Expert Opinion
on Treatment with nab-Paclitaxel plus Gemcitabine
Arndt Vogel a Frank Kullmann b Volker Kunzmann c Salah-Eddin Al-Batran d Helmut Oettle e Ruben Plentz f Jens Siveke g Christoph Springfeld h Hanno Riess i
a Klinik
für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Germany;
Medizinische Klinik I, Klinikum Weiden, Weiden i.d. OPf., Germany;
c
Medizinische Klinik und Poliklinik II, Schwerpunkt Medizinische Onkologie, Universitätsklinikum Würzburg, Germany;
d Krankenhaus Nordwest, University Cancer Center Frankfurt/M., Germany;
e Onkologische Schwerpunktpraxis, Friedrichshafen, Germany;
f
University Clinics Tübingen, Germany;
g Medizinische Klinik II, Klinikum rechts der Isar, Technical University Munich, Germany;
h National Center for Tumor Diseases, Heidelberg University Hospital, Germany;
i Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité, Universitätsmedizin Berlin, Germany
b
Summary
In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years,
new treatment options such as the FOLFIRINOX regimen
(5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or
the combination of nanoparticle albumin-bound (nab)paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in
patients with good performance status. Unfortunately,
patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients,
have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical
treatment of this patient group is limited. In a meeting of
German medical oncology experts, the available clinical
evidence and own clinical experience regarding the
management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present
publication summarises the discussion outcomes with
Arndt Vogel, Frank Kullmann, Volker Kunzmann and Hanno Riess were writing authors
and contributed equally to this article. All authors were members of the task force.
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regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best
available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the
experts provide advice for an initial dose reduction of
chemotherapy with nab-paclitaxel/gemcitabine based on
the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.
© 2015 The Author(s)
Published by S. Karger GmbH, Freiburg
Introduction
Treatment of Advanced Pancreatic Cancer
Pancreatic carcinoma ranks among the top 5 mortal cancers for
both sexes in Europe, despite a relatively low average incidence of
6.8/100,000 [1]. Pancreatic cancer is rare in adults < 40 years of age,
with a median age at diagnosis of 71 years [2]. As symptoms usually only appear once the disease has progressed, approximately
Prof. Dr. med. Hanno Riess
Charité – Universitätsmedizin Berlin
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie
Charitéplatz 1, 10117 Berlin, Germany
[email protected]
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Keywords
Albumin-bound paclitaxel · Cholestasis · Liver disease ·
Pancreatic cancer · Pharmacokinetics
Hyperbilirubinaemia in Patients with Pancreatic Cancer
Around 60–70% of pancreatic cancers are located in the pancreatic head [2], leading to hyperbilirubinaemia caused by obstruction
of the central bile duct in 70–80% of these patients [5]. Biliary obstruction and the resulting hyperbilirubinaemia usually complicate
the management of patients by increasing the risk of cholangitis
and causing frequent hospitalisations [11]; hyperbilirubinaemia
has been associated with shorter overall survival in patients with
pancreatic cancer [12, 13]. Biliary decompression in patients with
Management of Patients with Advanced
Pancreatic Cancer and Hyperbilirubinaemia
obstructive hyperbilirubinaemia is commonly performed using endoscopic stent placement [10], which not only reduces morbidity
[14] but also facilitates treatment with chemotherapy by allowing
total bilirubin levels to drop to ≤ 1.5–2 times the upper limit of
normal (≤ 1.5–2 × ULN). Other possible causes of hyperbilirubinaemia in patients with pancreatic cancer are obstruction of the
peripheral intrahepatic bile ducts due to tumour metastases, without major impairment of other aspects of liver function, or massive
infiltration of the liver by tumour metastases resulting in non-cirrhotic liver failure.
Unmet Need for Medical Treatment of Patients with Advanced
Pancreatic Cancer and Hyperbilirubinaemia
Many phase I, II and III studies have excluded patients with abnormal serum liver biochemical tests, including elevated bilirubin,
thus probably falsely excluding a considerable patient population
from potentially beneficial therapies [15]. Therefore, our knowledge
on the most appropriate starting doses of chemotherapy in these
individuals is limited [15]. Likewise, pivotal clinical trials with nabpaclitaxel plus gemcitabine have only included patients with bilirubin levels within the normal range [8, 16]. With the exception of
single case reports [17], there is currently no evidence from clinical
studies to support nab-paclitaxel plus gemcitabine treatment in patients with pancreatic cancer and elevated bilirubin. Thus, according to the current recommendation in the European summary of
product characteristics, treatment with nab-paclitaxel is not recommended in pancreatic cancer patients with moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and aspartate aminotransferase ≤ 10 × ULN) since there are insufficient data to permit dosage recommendations [18]. Despite its long-standing use in
clinical practice, similar restrictions exist for the recommendation
of gemcitabine: Due to insufficient information from clinical studies to allow for clear dose recommendations for this patient population, gemcitabine should be administered with caution in patients
with hepatic insufficiency [19]. An ongoing phase I study with nabpaclitaxel plus gemcitabine in patients with advanced pancreatic
cancer who have cholestatic hyperbilirubinaemia secondary to bile
duct obstruction [20] will hopefully shed more light on the impact
of hyperbilirubinaemia on the efficacy and safety of nab-paclitaxel
plus gemcitabine. In this publication, experienced experts will give
some guidance for the management of patients with advanced pancreatic cancer and hyperbilirubinaemia, especially regarding chemotherapy with nab-paclitaxel plus gemcitabine.
Materials and Methods
Data were retrieved from the published literature indexed in MEDLINE/
PubMed. The information was accessed until March 2015. For consensus development, a task force of clinical experts and practicing oncologists in the field of
medical oncology with long-standing expertise in the management of patients
with pancreatic cancer was established. The task force members discussed the
available clinical evidence, reported their clinical practice and agreed on a consensus statement based on a face-to-face meeting in January 2015. A core group
of experts summarised the current state of the art of management of patients
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85–90% of patients have unresectable disease at diagnosis [3] and
thus a low overall 5-year survival rate of less than 5% [4]. Tumour
resection remains the only curative treatment but is only suitable
for the minority of patients with early disease [5]. Even after complete resection followed by adjuvant chemotherapy, around 80% of
the patients will die within 5 years [6].
The available treatment options for patients with advanced, initially unresectable, relapsed or metastasised pancreatic cancer are
still far from satisfactory. The introduction of combination chemotherapies within the last 4 years, such as the multidrug combi­
nation of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin
(FOLFIRINOX) [7] and the combination of nanoparticle albuminbound (nab)-paclitaxel plus gemcitabine [8], has nevertheless offered a clinically relevant survival benefit over gemcitabine
monotherapy, the former treatment standard for more than 15
years. In a phase III study with selected patients from specialised
centres, FOLFIRINOX chemotherapy led to a substantial benefit in
overall survival compared to gemcitabine monotherapy (11.1 vs.
6.8 months; hazard ratio (HR) for death = 0.57 (95% confidence
interval (CI): 0.45–0.73); p < 0.001), although it was also associated
with a marked potential for toxicities and was limited to patients
≤ 75 years of age [7, 9]. In an international large-scale phase III
study, the combination of nab-paclitaxel plus gemcitabine was associated with a clinically relevant prolongation of overall survival
compared to gemcitabine alone (8.7 vs. 6.6 months; HR for death =
0.72 (95% CI: 0.62–0.83); p < 0.001) [8]. Although treatment with
nab-paclitaxel plus gemcitabine involved adverse reactions including haematological cytopenias and peripheral neuropathy, the tolerability profile was considered as manageable [8, 9]. The recently
updated US National Comprehensive Cancer Network (NCCN)
guideline recommends FOLFIRINOX and nab-paclitaxel plus
gemcitabine as the preferred treatment options for patients with
good performance status and metastatic disease and as possible options for the treatment of locally advanced, unresectable pancreatic
cancers [10]. Thus, at present, FOLFIRINOX or nab-paclitaxel plus
gemcitabine are considered the standard treatment for patients
with good performance status who do not have severe comorbidities [2]. Although a head-to-head comparison of both treatment
regimens is not available, chemotherapy with nab-paclitaxel plus
gemcitabine seems to be less toxic than FOLFIRINOX treatment
[9] and is not restricted to patients ≤ 75 years of age [8]. Consequently, we herein focus on recommendations for treatment with
nab-paclitaxel plus gemcitabine since it may be used for a broader
patient population compared to FOLFIRINOX.
Table 1. Selection of
laboratory tests in patients with hyperbilirubinaemia
Liver function defect
Parameter
Explanation
Hepatocellular damage
elevated liver transaminases (ALT, AST)
enzymes released when hepatocytes are damaged;
ALT more specific to hepatocytes than AST
elevated GLDH
expressed in mitochondria of liver parenchyma cells;
released upon liver cell necrosis
reduced serum albumin
most abundant plasma protein that is exclusively
synthesised in the liver; more common in chronic liver
disease than in acute toxicity
increased INR/prothrombin time or
reduced factor V
prothrombin (vitamin K dependent) and factor V
(vitamin K independent): examples of blood coagulation
factors synthesised in the liver; decreased concentration
leads to blood coagulation deficiency
reduced serum cholinesterase
elevated unconjugated bilirubin
enzyme mainly synthesised in hepatocytes
decreased glucuronidation capacity of the cirrhotic
liver
elevated conjugated bilirubin
reflux of bilirubin glucuronides into plasma due to
intra- or posthepatic obstruction
elevated ALP
increased synthesis of plasma ALP in case of any form
of biliary obstruction; elevated to a lesser degree in
hepatocellular injury
elevated GGT
differentiation of the source (liver or bone) of elevated
ALP: liver dysfunction if GGT increase ≥ 2 times the
increase in ALP; greatly increased in hepatocyte damage
and cholestasis
erythromycin breath test [15]
quantitative measure of CYP450 3A4 activity;
not routinely applied in clinical practice
Liver synthetic function
Cholestasis/
obstruction
CYP450 metabolism
with pancreatic cancer and hyperbilirubinaemia and verbalised the German
perspective on the treatment of this patient population with nab-paclitaxel plus
gemcitabine.
Results
Determining the Underlying Cause of Hyperbilirubinaemia in
Patients with Pancreatic Cancer
Bilirubin, a breakdown product of haemoproteins, is taken up
from plasma into liver hepatocytes where it is conjugated to glucuronic acid; the conjugated form is excreted into bile [21]. The upper
limit of the reference range of total bilirubin amounts to 1.2 mg/dl
(21 μmol/l) [22] and jaundice can be detected when the plasma concentration is 2–3-fold elevated [23]. The reasons for an elevated
serum bilirubin concentration can be grouped into 3 main categories: (1) prehepatic dysfunction, e.g. haemolysis, resulting in unconjugated hyperbilirubinaemia, (2) intrahepatic dysfunction, e.g. intrahepatic biliary obstruction or liver damage caused by hepatotoxic
drugs, leading to predominantly conjugated hyperbilirubinaemia,
and (3) posthepatic biliary obstruction resulting in predominantly
conjugated hyperbilirubinaemia [21, 24]. As outlined, in the majority of patients with pancreatic cancer, hyperbilirubinaemia is caused
by obstruction of the common bile duct due to a tumour in the pancreas head [5]. In patients with extensive liver metastasis, bilirubin
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Oncol Res Treat 2015;38:596–603
might be elevated due to intrahepatic biliary obstruction and/or
metastasis-related liver insufficiency. Some patients might suffer
from hyperbilirubinaemia caused by pre-existing hepatic dysfunction, e.g. liver cirrhosis [21, 25]. The prerequisite for the appropriate management of affected patients is to clearly determine the underlying cause of hyperbilirubinaemia. Therefore, a combination of
laboratory parameters should be analysed since patterns of abnormalities are more meaningful than elevations or reductions of individual parameters [21] (table 1). Since the laboratory test results in
most cases do not exactly identify the aetiology of predominant
conjugated hyperbilirubinaemia, imaging techniques including sonography, computed tomography (CT) and magnetic resonance
imaging (MRI) are essential to precisely determine the specific
problem [24]. In order to direct therapy and to predict the survival
of patients with chronic liver disease, scoring systems have been developed [26]. The long-established Child-(Turcotte-)Pugh score divides patients into classes A–C, based on the extent of clinical ascites, encephalopathy and laboratory parameters including albumin, the international normalised ratio (INR) and bilirubin [27,
28]. The model for end-stage liver disease (MELD) score is based on
a mathematical equation incorporating the bilirubin concentration,
the INR and the serum creatinine level [29]. Recently, the albuminbilirubin (ALBI) grade was developed. This is a mathematical equation incorporating only the serum bilirubin and albumin levels and
thus eliminating the need for subjective variables such as ascites and
encephalopathy [30].
Vogel/Kullmann/Kunzmann/Riess/Al-Batran/
Oettle/Plentz/Siveke/Springfeld
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ALT = Alanine aminotransferase, AST = aspartate aminotransferase, GLDH = glutamate dehydrogenase, INR = international
normalised ratio, ALP = alkaline phosphatase, GGT = gamma-glutamyltransferase.
Stent type
Duration
of patency
Remov­ability
Migration
probability
Device
costs
Cost-effectiveness
Plastic stent
short
easy
low
low
low due to higher number of
endoscopic procedures
extremely
difficult
low
Uncovered selfexpandable metal
stent
Covered selfexpandable metal
stent
long
easy
Panel Advice
– The underlying cause of hyperbilirubinaemia should be
clearly determined before initiation of chemotherapy.
– Since measurements of bilirubin or other laboratory tests
may not exactly identify the aetiology of hyperbilirubinaemia, imaging techniques such as ultrasound and/or CT
should be additionally applied.
Biliary Decompression in Patients with Pancreatic Cancer and
Obstructive Hyperbilirubinaemia Intended for Chemotherapy
The rationale for biliary decompression in patients with unresectable pancreatic cancer and obstructive cholestasis is the normalisation of the bilirubin levels to allow palliative chemotherapy,
and the prevention of other adverse outcomes such as cholangitis
and frequent hospitalisations [11]. According to the current German, European and American treatment guidelines, stent placement via endoscopic retrograde cholangiopancreatography
(ERCP) is the preferred method for biliary decompression in
these patients [5, 10, 31]. In case ERCP is not possible, percutaneous transhepatic biliary drainage (PTCD) is recommended [5, 10,
31]. Endoscopic ultrasound-guided transoesophageal or transduodenal biliary drainage represents a treatment alternative in selected patients not suitable for conventional ERCP and PTCD
[32, 33].
Basically, 3 types of stents can be used: plastic stents, uncovered
self-expandable metallic stents and covered self-expandable metallic stents [11]. The choice of stent depends on several aspects such
as the anatomical situation, the experience of the endoscopist, the
expected survival time and cost-effectiveness (table 2). Based on
the longer patency time compared to plastic stents, self-expanding
metal stents (either covered or uncovered) may be the preferred
option for patients with a life expectancy of > 3 months, according
to the treatment guidelines [5, 31].
While there is no discussion regarding prophylactic perioperative administration of antibiotics in conjunction with hepatobiliary surgery [31], antibiotic coverage during stent implantation is
still a matter of debate. Although severe complications with
ERCP procedures are rare, infectious complications remain prevalent [39]. Although no randomised study has been conducted to
test the benefit of peri-interventional infection prophylaxis, anti-
Management of Patients with Advanced
Pancreatic Cancer and Hyperbilirubinaemia
high
high
high in patients with expected
survival ≥ 4.8 to 6 months
[35–38]
biotic prophylaxis should be considered since biliary drainage
leads to bacterial contamination of the bile ducts in almost 100%
of cases [40].
Panel Advice
– Biliary decompression by endoscopic stenting is an essential
part of the palliative treatment of patients with obstructive
cholestasis.
– Stenting with either a metal or a plastic stent can be recommended. The choice of stent mainly depends on the anatomical situation and the expected survival time.
–Hospital-adjusted peri-interventional antibiotic prophy­
laxis should be considered.
Impact of Hyperbilirubinaemia on the Efficacy and Tolerability
of Chemotherapy with nab-Paclitaxel plus Gemcitabine
Hepatic dysfunction in patients with pancreatic cancer may affect the pharmacokinetic properties of drugs in different ways. A
reduced metabolic capacity of the liver, especially with respect to
cytochrome P450 (CYP450) isoenzymes, may change their hepatic
clearance [21]. Depending on the metabolic profile, this could either result in impaired bioactivation of a prodrug or in impaired
drug inactivation [21]. Obstruction of the common bile duct may
interfere with the clearance of drugs excreted via bile [41]. Portalvein thrombosis caused by a hypercoagulable state or by portalvein infiltration may compromise vascular supply to healthy liver
parenchyma and thereby impair drug metabolisation [21]. Consequently, interference with the drug kinetics in patients with hepatic
dysfunction may result in reduced effectiveness or increased toxicity of the chemotherapy [21]. Compounds metabolised via CYP450
isoenzymes and secreted via bile are especially affected.
nab-Paclitaxel
Originally, the paclitaxel formulation was based on the solvent
Cremophor EL (polyoxyethylated castor oil + dehydrated ethanol)
to increase the solubility and bioavailability of paclitaxel. A major
drawback of chemotherapy with this formulation is the occurrence
of adverse effects including hypersensitivity reactions and neurotoxicity, which are caused by the solvent [42, 43]. Encapsulation of
paclitaxel into albumin nanoparticles (nab-paclitaxel) allowed for
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Table 2. Pros and
cons of available stents
(modified from [11, 34])
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Oncol Res Treat 2015;38:596–603
versely correlated with the total bilirubin levels [54]. The study supports the same dose modification scheme in patients with hepatic
dysfunction as recommended for solvent-based paclitaxel [54].
However, its main limitations are that a control group of patients
with normal hepatic function was lacking and – as is the case for
the studies with solvent-based paclitaxel – that the population was
mixed with respect to the underlying aetiology of hyperbilirubinaemia [54]. Recently, a meta-analysis of 8 clinical studies of nab-paclitaxel was conducted: In 150 patients with different solid tumours,
mostly melanoma (29%) and breast cancer (16%), 13.3% of the patients had hyperbilirubinaemia [52]. In patients with total bilirubin
of > 1 to ≤ 1.5 × ULN, the elimination rate of nab-paclitaxel was not
significantly reduced [52]. Total bilirubin concentrations > 1.5 to
≤ 3 × ULN or > 3 to ≤ 5 × ULN led to a 22% or 26% decrease in the
maximum elimination rate of paclitaxel and to an approximately
20% increase in the mean paclitaxel area under the curve (AUC)
[52]. Thus, in contrast to the results of the pilot study [54], changes
in total bilirubin had only limited effect on paclitaxel elimination
[52]. According to the results of the meta-analysis, a 20% reduction
of the nab-paclitaxel dose may be considered a safe starting level for
patients with total bilirubin of > 1.5 to ≤ 5 × ULN to avoid a potential increase in systemic drug exposure [52]. Regarding treatment of
metastatic breast cancer, this recommendation has been approved
by the European authorities and was added to the summary of
product characteristics of nab-paclitaxel [18]. Nevertheless, similar
to the pilot study, the validity of this study for the treatment of pancreatic cancer patients is limited due to the small sample size. Furthermore, patients with pancreatic cancer and mechanic obstruction of the bile duct were not included in the analysis [52].
Gemcitabine
Paclitaxel and gemcitabine do not share a common metabolic
pathway, making pharmacokinetic interactions unlikely. Gemcitabine (difluorodeoxycytidine) is a nucleoside analogue prodrug
requiring intracellular activation by phosphorylation to di- and
triphosphates [19]. The compound is rapidly inactivated by cytidine deaminase to its main metabolite difluorodeoxyuridine and
99% of the administered dose is eliminated via renal excretion [19].
Treatment with gemcitabine leads to mild, mostly asymptomatic
and transient increases in transaminases in about two-thirds of the
patients, and in serum bilirubin in a small proportion of patients
[55]. However, rare cases of mostly fatal liver failure in association
with gemcitabine therapy have been previously observed – presumably caused by a metabolic idiosyncratic reaction to the compound [56, 57]. Consequently, careful monitoring of hepatic parameters during therapy with gemcitabine is recommended [21].
To study the impact of hepatic dysfunction on gemcitabine-­
induced toxicity, a prospective dose escalation study of the standard 30-min infusion was performed in 40 patients with hepatic
­impairment and total bilirubin levels of 1.7–5.7 mg/dl, of whom 17
patients had metastatic gastrointestinal cancer [58]. Patients with
hyperbilirubinaemia at baseline were prone to develop substantial
but mostly transient increases in the concentrations of bilirubin
and liver transaminases [58]. Thus, a reduction of the gemcitabine
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solvent-free administration of the lipophilic compound, thus
avoiding the toxicity associated with the solvent [42]. Pharma­
cokinetic studies with solvent-based paclitaxel revealed that the
compound is metabolised via hydroxylation by CYP450 iso­
enzymes to the main metabolite 6-α-hydroxypaclitaxel (CYP2C8)
and to 3’-p-hydroxypaclitaxel (CYP3A4), as well as 6-α,3’p-dihydroxypaclitaxel (CYP2C8 and CYP3A4). Around 70% of the
administered dose is eliminated via biliary excretion [18, 44, 45].
The hydroxy metabolites of paclitaxel are less cytotoxic than the
parent compound [44].
Few small studies on the influence of hepatic dysfunction and hyperbilirubinaemia on the pharmacokinetic properties and the toxicity of solvent-based paclitaxel have been performed. Consistent with
its mentioned metabolic profile, population-based pharmacokineticpharmacodynamic analyses involving patients with solid tumours
and varying degrees of hepatic impairment revealed a negative impact of hyperbilirubinaemia on the clearance of paclitaxel: An increase of 0.6 mg/dl (10 μmol) in total bilirubin was associated with a
12–19% decrease of the elimination capacity of paclitaxel [46–48].
These findings are in agreement with clinical data showing that paclitaxel treatment of patients with hepatic impairment and hyperbilirubinaemia was associated with a higher incidence of haematological and non-haematological toxic effects [49, 50], especially in
patients with more advanced hepatic impairment [48]. A pharmacokinetic-pharmacodynamic model, derived from one of the mentioned studies in 35 patients with solid tumours receiving paclitaxel
monotherapy, predicted the following recommendation for the initial paclitaxel dose based on the total bilirubin level: ≤ 1.25 × ULN:
175 mg/m2 (100% dose), 1.26–2.0 × ULN: 115 mg/m2 (66%), 2.1–3.5
× ULN: 100 mg/m2 (57%) and 3.6–10 × ULN: 70 mg/m2 (40%) [48].
The validity of the recommendation for an initial paclitaxel dose of
40% was confirmed in a pharmacokinetic study in 9 patients with
severe hepatic dysfunction caused by liver metastases and a bilirubin
level of 3–11 × ULN: Treatment with 70 mg/m2 paclitaxel was safe
and led to adequate plasma concentrations [51].
However, interpretation of the results derived from these
­studies using solvent-based paclitaxel is difficult due to the small
sample size and the large heterogeneity of included patients, especially regarding the kind of hepatic dysfunction – the underlying
aetiology of hyperbilirubinaemia has not been reported. In addition, data obtained with solvent-based paclitaxel are not directly
applicable to solvent-free nab-paclitaxel because of the different
distribution and elimination kinetics of the 2 formulations: nabpaclitaxel exhibits a faster distribution and a 9-fold larger distribution volume, as well as a slower elimination compared to solventbased paclitaxel [52]. The more rapid tissue distribution of paclitaxel when administered as nab-paclitaxel results in a shorter duration of high systemic drug concentrations, which likely contributes
to its reduced haematotoxicity in comparison to solvent-based paclitaxel [52]. Furthermore, administration of nab-paclitaxel led to
33% higher intratumoral drug accumulation in animal studies [53].
In accordance with the results for solvent-based paclitaxel [46–
48], a pilot study in 15 patients with solid tumours and hyperbilirubinaemia showed that nab-paclitaxel clearance was significantly in-
Table 3. Panel recommendation for initial
doses of nab-paclitaxel
and gemcitabine in
­patients with advanced
pancreatic cancer based
on the underlying cause
of hyperbilirubinaemia
Total bilirubin level
nab-Paclitaxel
dose, mg/m2
Patient group
Parameters for treatment
decision
Patients with biliary
obstructiona
≤ 3 × ULN
125
albumin level > 3.5 g/dl;
1,000
INR < 2.0 (vitamin K deficiency
> 3 to ≤ 8 × ULN
100
800
to be considered; substitution if
necessary)
≤ 1.5 × ULN
125
patient-related factors
1,000
(including performance status,
> 1.5 to ≤ 3 × ULN
100
800
co-morbidities, expectations);
> 3 to ≤ 5 × ULN
 75
600
(treatment only with
liver parameters (including
albumin, INR, cholinesterase)
specific care)b
no dosage recommendation; each patient to be treated individually based on underlying hepatic
­dysfunction
Patients with extensive
liver metastasis
Patients with pre-existing
chronic liver disease
Gemcitabine
dose, mg/m2
starting dose to 800 mg/m2 (= 80% of the standard dose) was recommended [58]. A small phase II study in 43 patients with advanced unresectable hepatobiliary carcinomas revealed a high frequency (30%) of grade 3/4 thrombocytopenias in the 18 patients
with hepatocellular carcinoma and liver cirrhosis (Child A: n = 5,
Child B: n = 13) of this group [59]. In contrast, a smaller study
­involving 9 patients with pancreatic (n = 5) or biliary tract cancer
(n = 4) and hepatic impairment showed that the full dose of gemcitabine can be safely used in patients with elevated total bilirubin
and transaminases when administered via the slower 10-mg/m2/
min infusion [60]. Another recent study in 12 patients with advanced pancreatic (n = 7) or biliary tract cancer (n = 5) and extraor intrahepatic cholestasis, receiving gemcitabine plus capecitabine
chemotherapy, revealed a further interesting aspect: A total bilirubin level of ≥ 2 × ULN was associated with an impaired intracellular activation of gemcitabine to gemcitabine triphosphates, suggesting limited anti-tumour activity [61]. A larger study to confirm
this finding is warranted.
Panel Advice
– nab-Paclitaxel and gemcitabine should be used with caution
in patients with hyperbilirubinaemia. Careful monitoring of
liver parameters during chemotherapy is warranted.
– Due to different pharmacokinetic properties, data derived
from studies with solvent-based paclitaxel cannot be directly transferred to nab-paclitaxel.
– The main limitations of the available studies are their small
sample sizes and the large heterogeneity of the included patients, especially regarding aetiology and degree of hepatic
impairment.
– The underlying cause of hyperbilirubinaemia and the metabolisation route of the cytotoxic agents have to be considered before initiation of chemotherapy.
Management of Patients with Advanced
Pancreatic Cancer and Hyperbilirubinaemia
Treatment Advice for Chemotherapy with nab-Paclitaxel plus
Gemcitabine in Patients with Advanced Pancreatic Cancer and
Hyperbilirubinaemia
Based on the underlying cause of hyperbilirubinaemia, patients
with pancreatic cancer and elevated total bilirubin can be grouped
into individuals with (1) biliary obstruction (mostly caused by a tumour in the pancreas head), (2) extensive liver metastasis and (3)
pre-existing chronic liver disease. The percentages of patients in
the 3 groups receiving first-line chemotherapy were estimated by
the panel to be approximately 70%, 20% and 10%, respectively. According to the current guidelines, the prerequisite for initiation of
chemotherapy is as much biliary decompression as possible [10].
The expert panel recommends starting treatment as soon as the
bilirubin concentration is sufficiently decreased or further decreasing, since the time between first diagnosis and treatment start may
be of prognostic relevance [62]. Due to the increased risk of infections after stent insertion [39] and the risk of leucopenia associated
with chemotherapy [8], risks and benefits of an early treatment
start, as well as favouring a standard or a reduced starting dose of
chemotherapy, have to be weighed against each other. In this context, antibiotic prophylaxis has to be considered. As disease remission is the primary treatment goal, the expert panel prefers to use
the combination treatment with nab-paclitaxel plus gemcitabine at
a reduced starting dose over gemcitabine monotherapy in patients
with hyperbilirubinaemia. The experts’ recommendation for starting doses of nab-paclitaxel and gemcitabine in patients with biliary
obstruction or extensive liver metastasis based on the total bilirubin level and other parameters is summarised in table 3. Patients
with pre-existing chronic liver disease, e.g. liver fibrosis or cirrhosis, are a very heterogeneous patient population with respect to remaining liver function. Therefore, the experts do not provide a
general treatment recommendation in this patient group; each individual case should be carefully evaluated. According to the German S3 treatment guideline for pancreatic cancer, treatment with
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Consider transferring the patient to an experienced study centre for the first treatment cycle; re-evaluate dose intensity (reduction/­
escalation) prior to every application dependent on treatment-associated toxicity, actual bilirubin level and treatment effect.
aChemotherapy can be considered as soon as the bilirubin concentration is sufficiently decreased after biliary decompression and
­stable or further decreasing.
bBecause of the highly critical situation, patients should be treated with specific care. Very close monitoring is required.
INR, International normalised ratio; ULN, upper limit of normal.
adjuvant chemotherapy is unrestricted in patients with Child A
liver cirrhosis but not recommended in patients with Child B and
C liver cirrhosis [31].
Conclusions
Many patients with advanced pancreatic cancer suffer from hyperbilirubinaemia [5], and these constitute a substantial population
that has been excluded from most clinical studies [15]. Consequently, treatment of these individuals is complicated as the
knowledge of appropriate starting doses of chemotherapy is limited to single case reports or small clinical studies in largely heterogeneous patient populations with regard to the tumour type and
underlying aetiology of hyperbilirubinaemia [15]. The recommendations provided by the German expert panel are based on the best
available evidence from clinical studies and their long-standing
clinical experience in the management of patients with pancreatic
cancer. Most importantly, since hyperbilirubinaemia can be a
symptom of different types of hepatic dysfunction, its underlying
aetiology should be clearly determined before initiation of chemotherapy. Furthermore, the metabolisation routes of the cytotoxic
agents must be considered. Due to the possible impact of hepatic
impairment on the pharmacokinetic route of nab-paclitaxel and
gemcitabine that was shown in small clinical studies, these compounds should be used with caution in patients with hyperbilirubinaemia, and careful monitoring of patients and liver parameters
during chemotherapy is warranted. It should be kept in mind that
data derived from studies with solvent-based paclitaxel cannot be
directly transferred to nab-paclitaxel due to large differences in the
pharmacokinetic properties of these 2 formulations. In general, the
experts provide advice on reduced starting doses of nab-paclitaxel
and gemcitabine based on the total bilirubin level when initiating
chemotherapy in patients with biliary obstruction or with extensive
liver metastasis (summarised in table 3). Due to large heterogeneity
regarding the remaining liver function of patients with pre-existing
chronic liver disease, no general treatment recommendation for
this patient group can be made.
In summary, effective treatment options including nab-paclitaxel plus gemcitabine should also be made available for patients
with advanced pancreatic cancer and primary disease-associated
conditions such as hyperbilirubinaemia – provided that the appropriate precautions are considered.
Acknowledgements
The authors thank Jutta Walstab, Physicians World Europe GmbH, Mannheim, Germany for providing medical writing assistance in the preparation of
this manuscript, supported by Celgene GmbH, Munich, Germany. The authors
directed and are fully responsible for all content and editorial decisions for this
manuscript.
Disclosure Statement
A.V.: Honoraria for lectures and consultancy and travel grants from Celgene and Roche; F.K.: honoraria for lectures and consultancy and travel grants
from Celgene, Lilly, Roche, Sanofi and Merck; V.K.: honoraria for lectures and
consultancy from Celgene, Roche and Merck; H.R.: honoraria for lectures and
consultancy and travel grants from Amgen, Bayer, Celgene, Merck, Roche and
Sanofi-Aventis.
602
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Erratum
The correct order of authors of the article ‘Patients with Advanced Pancreatic Cancer and
Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine’ (Oncol Res Treat 2015;38:596–603; DOI: 10.1159/000441310) is:
Arndt Vogela Frank Kullmannb Volker Kunzmannc
Salah-Eddin Al-Batrand Helmut Oettlee Ruben Plentzf
Jens Sivekeg Christoph Springfeldh Hanno Riessi
a Klinik
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für Gastroenterologie, Hepatologie und Endokrinologie,
Medizinische Hochschule Hannover, Germany;
b Medizinische Klinik I, Klinikum Weiden, Weiden i.d. OPf., Germany;
c
Medizinische Klinik und Poliklinik II, Schwerpunkt Medizinische Onkologie,
Universitätsklinikum Würzburg, Germany;
d
Krankenhaus Nordwest, University Cancer Center Frankfurt/M., Germany;
e
Onkologische Schwerpunktpraxis, Friedrichshafen, Germany;
f University Clinics Tübingen, Germany;
g Medizinische Klinik II, Klinikum rechts der Isar, Technical University Munich, Germany;
h National Center for Tumor Diseases, Heidelberg University Hospital, Germany;
i Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie,
Charité, Universitätsmedizin Berlin, Germany